title: Gold activates mast cells via calcium influx through multiple H2O2-sensitive pathways including L-type calcium channels.
abstract: Heavy metals, including gold, induce severe contact hypersensitivity and autoimmune disorders, which develop through an initial Th2-independent process followed by a Th2-dependent process. It has been shown that mast cell activation plays a role in the Th2-independent process and that gold stimulates histamine release in vitro. However, the mechanisms of the gold-induced mast cell activation remain largely unclear. Here we report that gold directly activates mast cells in a Ca2+-dependent manner. HAuCl4 [Au(III)] at nontoxic concentrations (≤50 μM) induced substantial degranulation and leukotriene C4 secretion in an extracellular Ca2+-dependent manner. Au(III) induced a robust Ca2+ influx but not Ca2+ mobilization from internal stores. Au(III) also stimulated intracellular production of reactive oxygen species, including H2O2, and blockade of the production abolished the mediator release and Ca2+ influx. Au(III) induced Ca2+ influx through multiple store-independent Ca2+ channels, including Cav1.2 L-type Ca2+ channels (LTCCs) and 2-aminoethoxydiphenyl borate (2-APB)-sensitive Ca2+ channels. The 2-APB-sensitive channel seemed to mediate Au(III)-induced degranulation. Our results indicate that gold stimulates Ca2+ influx and mediator release in mast cells through multiple H2O2-sensitive Ca2+ channels including LTCCs and 2-APB-sensitive Ca2+ channels. These findings provide insight into the roles of these Ca2+ channels in the Th2-independent process of gold-induced immunological disorders.
authors.affiliation: Division of Molecular Cell Immunology and Allergology, Graduate School of Medical Science, Nihon University, and Department of Dermatology, Nihon University Surugadai Hospital, Tokyo 173-8610, Japan.
authors.forename: Koremasa
authors.initials: K
authors.lastname: Hayama
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Suzuki
authors.forename: Toshio
authors.initials: T
authors.lastname: Inoue
authors.forename: Toyoko
authors.initials: T
authors.lastname: Ochiai
authors.forename: Tadashi
authors.initials: T
authors.lastname: Terui
authors.forename: Chisei
authors.initials: C
authors.lastname: Ra
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D020746:Calcium Channels, L-Type / Q000378:metabolism*; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D006046:Gold / Q000494:pharmacology*; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism*; D008407:Mast Cells / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D020746:Calcium Channels, L-Type; D017382:Reactive Oxygen Species; D006046:Gold; D006861:Hydrogen Peroxide; D002118:Calcium